Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts

Rangasudhagar Radhakrishnan, Ji Hee Ha, Muralidharan Jayaraman, Jinsong Liu, Katherine M. Moxley, Ciro Isidoro, Anil K Sood, Yong Sang Song, Danny N. Dhanasekaran

Research output: Contribution to journalArticle

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Abstract

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)464-474
Number of pages11
JournalCancer Letters
Volume442
DOIs
StatePublished - Feb 1 2019

Fingerprint

Ovarian Neoplasms
Fibroblasts
Phenotype
Glycolysis
Conditioned Culture Medium
Lysophosphatidic Acid Receptors
lysophosphatidic acid
Cancer-Associated Fibroblasts
Lung
Ascitic Fluid
Maintenance
Neoplasm Metastasis
Therapeutics

Keywords

  • Cancer-associated fibroblasts
  • Glycolysis
  • HIF1
  • Hypoxia-inducible factor 1
  • Lysophosphatidic acid
  • Ovarian-cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts. / Radhakrishnan, Rangasudhagar; Ha, Ji Hee; Jayaraman, Muralidharan; Liu, Jinsong; Moxley, Katherine M.; Isidoro, Ciro; Sood, Anil K; Song, Yong Sang; Dhanasekaran, Danny N.

In: Cancer Letters, Vol. 442, 01.02.2019, p. 464-474.

Research output: Contribution to journalArticle

Radhakrishnan, Rangasudhagar ; Ha, Ji Hee ; Jayaraman, Muralidharan ; Liu, Jinsong ; Moxley, Katherine M. ; Isidoro, Ciro ; Sood, Anil K ; Song, Yong Sang ; Dhanasekaran, Danny N. / Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts. In: Cancer Letters. 2019 ; Vol. 442. pp. 464-474.
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abstract = "Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.",
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AU - Radhakrishnan, Rangasudhagar

AU - Ha, Ji Hee

AU - Jayaraman, Muralidharan

AU - Liu, Jinsong

AU - Moxley, Katherine M.

AU - Isidoro, Ciro

AU - Sood, Anil K

AU - Song, Yong Sang

AU - Dhanasekaran, Danny N.

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N2 - Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

AB - Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

KW - Cancer-associated fibroblasts

KW - Glycolysis

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KW - Hypoxia-inducible factor 1

KW - Lysophosphatidic acid

KW - Ovarian-cancer

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